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It is not often realized that the absolute protein specificity is an exception rather than a rule. Two major kinds of protein multi-specificities are promiscuity and moonlighting. This review discusses the idea of enzyme specificity and then focusses on moonlighting. Some important examples of protein moonlighting, such as crystallins, ceruloplasmin, metallothioniens, macrophage migration inhibitory factor, and enzymes of carbohydrate metabolism are discussed. How protein plasticity and intrinsic disorder enable the removing the distinction between enzymes and other biologically active proteins are outlined. Finally, information on important roles of moonlighting in human diseases is updated.

The whitefly Bemisia tabaci is an important pest of worldwide agriculture. Previous work has shown that B. tabaci actively suppresses host plant defenses, but our knowledge of the specific mechanisms involved remains limited. Here we describe a B. tabaci salivary protein, the ferritin BtFer1, and its role in facilitating exploitation of host plants. We show that BtFer1 exhibits Fe2+ binding ability and ferroxidase activity, and that secretion of BtFer1 during B. tabaci feeding suppresses H₂O₂-generated oxidative signals in tomato (Solanum lycopersicum). Silencing BtFer1 enhanced the induction of the jasmonic acid (JA)-mediated defense signaling pathway in response to whitefly feeding, and led to increased callose deposition and the production of proteinase inhibitors that prevent whiteflies from continuously ingesting and digesting phloem sap. Consistent with these effects, silencing BtFer1 reduced whitefly survival on tomato but not on artificial diet. Using a JA-deficient spr2 mutant plant further showed that suppression of JA defenses by BtFer1 is sufficient to increase B. tabaci survival. Taken together, these results demonstrate that BtFer1 acts as an effector protein that mediates whitefly–tomato interactions. These findings represent an important step forward in understanding the molecular mechanisms by which whiteflies and other insect herbivores suppress host plant defenses.

The DNA‐binding protein from starved cells (Dps) is found in a wide range of microorganisms, and it has been well characterized. However, little is known about Dps proteins from nonheterocystous filamentous cyanobacteria. In this study, a Dps protein from the thermophilic nonheterocystous filamentous cyanobacterium Thermoleptolyngbya sp. O‐77 (TlDps1) was purified and characterized. PAGE and CD analyses of TlDps1 demonstrated that it had higher thermostability than previously reported Dps proteins. X‐ray crystallographic analysis revealed that TlDps1 possessed His‐type ferroxidase centers within the cavity and unique metal‐binding sites located on the surface of the protein, which presumably contributed to its exceedingly high thermostability. A DNA‐binding protein from starved cells (Dps) protein from nonheterocystous filamentous cyanobacterium Thermoleptolyngbya sp. O‐77 (TlDps1) was purified and characterized. PAGE and CD analyses of TlDps1 illustrated that it had higher thermostability than previously reported Dps proteins. X‐ray crystallographic analysis revealed that TlDps1 possessed His‐type ferroxidase centers within the cavity and unique metal‐binding sites located on the surface of the protein.

The mammalian multicopper ferroxidases (MCFs) ceruloplasmin (CP), hephaestin (HEPH) and zyklopen (ZP) comprise a family of conserved enzymes that are essential for body iron homeostasis. Each of these enzymes contains six biosynthetically incorporated copper atoms which act as intermediate electron acceptors, and the oxidation of iron is associated with the four electron reduction of dioxygen to generate two water molecules. CP occurs in both a secreted and GPI-linked (membrane-bound) form, while HEPH and ZP each contain a single C-terminal transmembrane domain. These enzymes function to ensure the efficient oxidation of iron so that it can be effectively released from tissues via the iron export protein ferroportin and subsequently bound to the iron carrier protein transferrin in the blood. CP is particularly important in facilitating iron release from the liver and central nervous system, HEPH is the major MCF in the small intestine and is critical for dietary iron absorption, and ZP is important for normal hair development. CP and HEPH (and possibly ZP) function in multiple tissues. These proteins also play other (non-iron-related) physiological roles, but many of these are ill-defined. In addition to disrupting iron homeostasis, MCF dysfunction perturbs neurological and immune function, alters cancer susceptibility, and causes hair loss, but, despite their importance, how MCFs co-ordinately maintain body iron homeostasis and perform other functions remains incompletely understood.

The contribution of arbuscular mycorrhizal fungi (AM fungi) to plant iron (Fe) acquisition has been demonstrated in several studies. A previous investigation revealed that the AM fungus Rhizophagus irregularis utilizes a high-affinity reductive pathway for Fe uptake, mediated by the Fe transporter RiFTR1. In this study, we used a genome-wide approach in R. irregularis to find genes encoding ferroxidases of the multicopper oxidase (MCO) gene family in an attempt to identify the ferroxidase partner of RiFTR1. Nine genes putatively encoding MCOs ( RiMCO1-9 ) were identified. Yeast complementation assays demonstrated that RiMCO1 and RiMCO3 can function as ferroxidases, suggesting their involvement in the reductive Fe uptake pathway. Surprisingly, RiFTR1 was capable of transporting Fe in yeast without a ferroxidase partner, resembling the Fe transport mechanism of plant IRT1-like systems. RiFTR1 exhibited increase expression in arbuscules. Overexpression of RiFTR1 in Medicago truncatula roots led to enhanced mycorrhizal colonization and arbuscule abundance, highlighting the significance of Fe for AM symbiosis.

Plants use nitrate and ammonium as major nitrogen (N) sources, each affecting root development through different mechanisms. However, the exact signaling pathways involved in root development are poorly understood. Here, we show that, in Arabidopsis thaliana , either disruption of the cell wall-localized ferroxidase LPR2 or a decrease in iron supplementation efficiently alleviates the growth inhibition of primary roots in response to NH 4 + as the N source. Further study revealed that, compared with nitrate, ammonium led to excess iron accumulation in the apoplast of phloem in an LPR2-dependent manner. Such an aberrant iron accumulation subsequently causes massive callose deposition in the phloem from a resulting burst of reactive oxygen species, which impairs the function of the phloem. Therefore, ammonium attenuates primary root development by insufficiently allocating sucrose to the growth zone. Our results link phloem iron to root morphology in response to environmental cues. Ammonium affects plant root development through different mechanisms than nitrate. Here, the authors show that the Arabidopsis cell wall-localized ferroxidase LPR2 is required to attenuate root growth in response to ammonium.

The copper compound Cu II (atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu II (atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for Cu II (atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for Cu II (atsm) involving copper availability may also be pertinent to sporadic cases of ALS.

Ceruloplasmin is a ferroxidase that interacts with ferroportin to export cellular iron, but is not expressed in neurons. We recently reported that the amyloid precursor protein (APP) is the analogous iron-exporting chaperone for neurons and other cells. The ferroxidase activity of APP has since been called into question. Using a triplex Fe2+ oxidation assay, we analyzed the activity of a soluble form of APP (sAPPα) within a buffer of physiological pH and anionic charge, and determined that iron oxidation originated from phosphate. Using various techniques such as flow-cytometry to measure surface presented proteins, we confirmed that endogenous APP is essential for ferroportin persistence on the neuronal surface. Therefore, despite lacking ferroxidase activity, APP still supports iron export from neurons.

Abstract Introduction/Objective Osteoporosis is a bone disorder and is currently a major global health issue. Ceruloplasmin (CP) is an acute phase reactant and antioxidant, characterized by ferroxidase activity and increases in inflammation. C-reactive protein (CRP), an acute phase protein belonging to pentraxin family of proteins. This study was designed to investigate the role of acute phase reactants Ceruloplasmin and CRP in the screening of osteoporosis. The objective of this paper is to evaluate the role of serum Ceruloplasmin and C-reactive protein as biomarkers of osteoporosis. Methods/Case Report This study was conducted in the Bone Clinic and the biochemistry department of a tertiary care hospital. One hundred and twenty participants were included in the study belonging to the age group of 50 to 80 years. Participants in the group were divided into two groups, group I: comprising of patients with osteoporosis, and group II: consisting of patients without osteoporosis (n=56) (control group) (n=64). Patients were classified into two groups on the basis of Bone Mineral Density measurements using dual-energy. X-ray absorptiometry scanning. CRP and serum CP levels were analyzed in blood samples by immunoturbidimetry. Results (if a Case Study enter NA) Serum ceruloplasmin levels were significantly higher in Osteoporosis patients as compared to the control group. A significant positive correlation (r= 0.92, p<0.05 ) was observed between higher serum levels of CP and higher levels of CRP in the Osteoporosis patients. There was a significant difference in the CP levels of the osteoporosis group (68.4± 7.2 mg/dl ) and the control group (37.3 ± 4.9 mg/dl) (p<0.05). CRP levels also differed significantly among the osteoporosis patients (2.23± 0.68 mg/dl) and the control participants (1.07± 0.42 mg/dl) (p<0.05). Conclusion Our study demonstrates that the measurement of serum ceruloplasmin levels has the potential as a surrogate marker for patients with osteoporosis

Aims/hypothesisIron accumulation affects obesity and diabetes, both of which are ameliorated by iron reduction. Ferritin, an iron-storage protein, plays a crucial role in iron metabolism. H-ferritin exerts its cytoprotective action by reducing toxicity via its ferroxidase activity. We investigated the role of macrophage H-ferritin in obesity and diabetes.MethodsConditional macrophage-specific H-ferritin (Fth, also known as Fth1) knockout (LysM-Cre Fth KO) mice were used and divided into four groups: wild-type (WT) and LysM-Cre Fth KO mice with normal diet (ND), and WT and LysM-Cre Fth KO mice with high-fat diet (HFD). These mice were analysed for characteristics of obesity and diabetes, tissue iron content, inflammation, oxidative stress, insulin sensitivity and metabolic measurements. RAW264.7 macrophage cells were used for in vitro experiments.ResultsIron concentration reduced, and mRNA expression of ferroportin increased, in macrophages from LysM-Cre Fth KO mice. HFD-induced obesity was lower in LysM-Cre Fth KO mice than in WT mice at 12 weeks (body weight: KO 34.6 ± 5.6 g vs WT 40.1 ± 5.2 g). mRNA expression of inflammatory cytokines and infiltrated macrophages and oxidative stress increased in the adipose tissue of HFD-fed WT mice, but was not elevated in HFD-fed LysM-Cre Fth KO mice. However, WT mice fed an HFD had elevated iron concentration in adipose tissue and spleen, which was not observed in LysM-Cre Fth KO mice fed an HFD (adipose tissue [μmol Fe/g protein]: KO 1496 ± 479 vs WT 2316 ± 866; spleen [μmol Fe/g protein]: KO 218 ± 54 vs WT 334 ± 83). Moreover, HFD administration impaired both glucose tolerance and insulin sensitivity in WT mice, which was ameliorated in LysM-Cre Fth KO mice. In addition, energy expenditure, mRNA expression of thermogenic genes, and body temperature were higher in KO mice with HFD than WT mice with HFD. In vitro experiments showed that iron content was reduced, and lipopolysaccharide-induced Tnf-α (also known as Tnf) mRNA upregulation was inhibited in a macrophage cell line transfected with Fth siRNA.Conclusions/interpretationDeletion of macrophage H-ferritin suppresses the inflammatory response by reducing intracellular iron levels, resulting in the prevention of HFD-induced obesity and diabetes. The findings from this study highlight macrophage iron levels as a potential therapeutic target for obesity and diabetes.